Esterification of Unprotected ꢀ-Amino Acids
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
43
amino acids, choosing some non-functionalized and with
primary amino group amino-acids: results are shown in
Table 4. For L-phenylalanine, L-tyrosine, L-valine, and L-
isoleucine results for conversion and yield are similar to L-
leucine, and for L-triptophan and L-alanine yields are a bit
lower, around 33-35% of pure ester.
sodium bicarbonate was added to the aqueous phase until a
pH of 8-9. This mixture was extracted with diethyl ether
(3ꢀ10 ml), with addition of ethyl acetate if solutions were
not limpid (this happened in the case of triptophane). The
combined organic extracts of the second extraction were
dried over Na2SO4 and analyzed by g.c (most times there is
only one product by g.c). After elimination of the organic
solvent by rotatory evaporation, the product was obtained,
pure and weighted (to determine the yield of the product). In
order to prevent inter- and intra-molecular reaction of the
ester with the time, the final products were converted rapidly
to tosylate salts. The esters, pure, were dissolved in diethyl
ether and a slightly more than equimolar quantity of p-
toluensulfonic acid was added (solution in diethyl ether).
White solids formed: they were kept at 4°C overnight and
then filtered under vacuum. The solids were dried under
vacuum over P2O5. The structures of the various esters were
confirmed by NMR of these salts.
In conclusion we have developed a simple, mild, rapid
and save method to afford ꢀ-amino acids benzylic esters
from unprotected amino acids and benzyl chloride, removing
all by-products by a simple working-up procedure. Yields
are not excellent being ca. 54%, and lower in some cases
(35% ca), but they are satisfactory because refer to the pure
weighted products, easily isolated. The scope and limitations
of our system for esterification are currently under
investigation. Results including esterifications of other
amino acids and dipeptides will be published in due course.
EXPERIMENTAL
General
ACKNOWLEDGEMENTS
All chemicals and solvents of analytical grade were
purchased by Sigma-Aldrich and used as received. Bu-
Support of this work by the Ministero dell'Istruzione,
Università e Ricerca, Rome, is gratefully acknowledged.
t
benzene (purity 99%) from Baker was used as internal
standard without further purification. The reaction
conversion was quantitatively examined by an Agilent
Technologies 6854 Series II gas chromatograph equipped
with a 30 m HP-1 capillary column, using Bu-benzene as
internal standard.
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Preparation of Amino Acid Benzyl Esters
The ionic liquid and the amino acid were introduced
under nitrogen and with mechanical stirring in 10 ml round-
bottom flask equipped with cap and septum, and then the
flask was closed. Benzyl chloride was added after closure of
the cap by injection of the liquid through the septum. The
mixture, that is homogeneous, limpid and colourless, was
then heated to 90°C and magnetically stirred. At the end of
reaction, after cooling to room temperature, tBu-benzene was
added, as internal standard. Water was added, and the
mixture was extracted with diethyl ether (3ꢀ10 ml), that
solubilized the untreated benzyl chloride, the internal
standard, and any neutral undesired by-product; test by g.c.
confirmed the absence of any product in further extraction.
At this point, the combined organic extracts were dried over
Na2SO4 and quantitatively analyzed by g.c. to get the degree
of conversion (relative to benzyl chloride). Thereafter solid
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